Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
2002-01-03
2003-08-05
Lankford, Jr., Leon B. (Department: 1651)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S725000, C514S023000, C514S168000
Reexamination Certificate
active
06602512
ABSTRACT:
The present invention relates to a composition for the prevention and treatment of muscular energetic deficiencies, states of asthenia and muscle fatigue, states of heart fatigue and post-infarct conditions and for enhancing sporting performances.
Accordingly, the composition may take the form and exert the action of a dietary supplement or of an actual medicine, depending upon the support or preventive action, or the strictly therapeutic action, which the composition is intended to exert in relation to the particular individuals it is to be used in.
More particularly the present invention relates to a n orally, parenterally, rectally or transdermally administrable combination composition which comprises as characterizing ingredients:
(a) at least on e carnitine s elected from the group consisting of L-carnitine, acetyl L-carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L-carnitine and isovaleryl L-carnitine or a pharmacologically acceptable salt thereof, and
(b) creatinol-phosphate or a pharmacologically acceptable salt thereof.
Compositions comprising carnitines and creatine or phosphocreatine are already known. WO 98/43499 (Sigma-Tau) discloses a nutritional supplement for facilitating the adaptation of skeletal muscle in individuals undergoing programs of strenuous exercise and counteracting defatigation and weariness in asthenic individuals, which comprises a combination of L-carnitine, acetyl L-carnitine and propionyl L-carnitine as basic active ingredients which may also comprise creatine and/or phosphocreatine as optionally additive components.
U.S. Pat. No. 4,376,117 (Simes) discloses the magnesium salt of creatinol-O-phosphate which is useful in the treatment and prevention of myocardiac infarction.
Both carnitine and creatinol-phosphate [1-(2-hydroxyethyl)-1-methylguanidine-O-phosphate] are well known for their important metabolic and pharmacological effects which have led to several positive pharmacological and clinical findings.
The carnitines are known to play a major role in the processes of beta-oxidation of fatty acids in the formation of ATP. They are also endowed with important antioxidant activity as demonstrated by their protective effect on lipid peroxidation of the cellular phospholipid membranes and on oxidative stress induced at the myocardial and endothelial cells level. These biochemical effects of the carnitines are reflected by the favourable results obtained in clinical practice with their use in the treatment of various forms of atherosclerosis. myocardial ischaemia, peripheral vasculopaties and diabete.
Creatinol-phosphate, which is a compound structurally akin to creatine phosphate, from which it differs in its greater stability and in various metabolic and pharmacodynamic aspects, belongs to that group of phosphagens which play a fundamental role in muscle energy processes. It is known, in fact, that creatine phosphate is strongly involved in the processes responsible, in muscles, for ATP synthesis which is reduced during muscular exercise.
Creatine, creatine phosphate, creatine phosphokinase, ATP and ADP are fundamental biochemical structures responsible for muscle function, particularly in anaerobic conditions. However, creatine, above all others, is the essential compound conditioning the remaining steps, its presence being of fundamental importance for achieving phosphorylation and the associated ATP-related energy processes. Its administration leads, in fact, to an increase in its muscular concentration and to an increase in creatine phosphate.
To obtain these effects in human subjects, however, the administration of high doses of creatine is necessary, up to and beyond 20 g per day, with consequent adverse side effects, particularly at the renal level. Even though only approximately a quarter of the creatine administered can be transformed into creatine phosphate, administration of the latter is not a practical proposition on account of its instability and the difficulty of oral administration. It would, therefore, appear to be of great interest to provide another phosphorous-bearing derivative belonging to the pool of organic phosphates which is endowed with great stability and excellent tolerability and can also be administered orally, such as creatinol-phosphate, the administration of which, even at low doses, induces a substantial increase in muscular creatine and the consequent formation of creatine phosphate. Its administration causes an increase in muscular strength in human subjects, which is also marked in the elderly, as well as the disappearance of asthenia and muscular weakness in convalescent subjects and the restoration of cardiac efficiency in subjects who have suffered an infarct.
Potentially even more interesting, however, also with a view to its action on muscular activity, are the results of experiments indicating its ability to stabilise the cell membranes which may be more resistant to attack by reactive oxygen species (ROS).
Since, as is known, one of the effects that forced muscular exercise may induce at muscle level are lesions of the muscle fibres themselves related to oxygen toxicity and to the products of lipid peroxidation, one of the favourable effects of creatinol-phosphate consists in its ability to protect the musculature against ROS-induced lesions.
It has now surprisingly been found that a combination composition comprising as its characterising components:
(a) at least one carnitine selected from the group consisting of L-carnitine, acetyl L-carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L-carnitine and isovaleryl L-carnitine or a pharmacologically acceptable salt thereof, and
(b) creatinol-phosphate or its pharmacologically acceptable salt, is extremely effective for the prevention and treatment of muscular energy deficiencies, states of asthenia and muscle fatigue, states of heart fatigue and postinfarct conditions, and for enhancing sporting performance, owing to the potent, unexpected synergistic effect exerted by its components.
Toxicology Tests
Both the carnitines and creatinol-phosphate are products known for their low toxicity and good tolerability.
In tests performed in rats, doses of L-carnitine and creatinol-phosphate in combination, corresponding to 250 mg/kg of each compound, were administered intraperitoneally without the occurrence of any signs of toxicity. Likewise, no signs of toxicity were detected when 750 mg/kg of L-carnitine were administered orally in combination with 750 mg/kg of creatinol-phosphate. Even prolonged oral administration for one month of 200 mg/kg of L-carnitine plus 200 mg/kg of creatinol-phosphate to rats did not cause any toxic intolerance reaction. Full blood counts and blood-chemistry tests performed at the end of treatment also failed to reveal any abnormalities worthy of note as compared to controls. At autopsy, none of the main organs showed any signs of distress. Histological and histochemical investigations confirmed these findings, the results being comparable to those obtained in the control animals.
Muscle Fatigue Test
The method described by Zheng (Zheng R. L., Acta Pharmacol. Sinica, 14, 47, 1993) was used for this test in order to observe whether the administration of L-carnitine or creatinol-phosphate or of the two products in combination might increase reaction time in treated animals as compared to controls.
In this test, different groups of mice received daily oral doses of 200 mg/kg of L-carnitine or 200 mg/kg of creatinol-phosphate or of the two compounds in combination over the 6-day period preceding the test. The animals were immersed in a tank full of water and swimming endurance time was measured.
Both L-carnitine and creatinol-phosphate increased swimming endurance time, but the greatest effect was observed in mice treated with the L-carnitine plus creatinol-phosphate combination. In these latter animals, in fact, swimming endurance time was significantly longer compared to controls, thus confirming the synergistic effect exerted by the components of the composition (see Table 1).
TABLE 1
Muscle fat
Davis Ruth A.
Lankford , Jr. Leon B.
Nixon & Vanderhye P.C.
Sigma-Tau HealthScience S.p.A.
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